Activation of Insulin Signaling by Botanical Products.

Type 2 diabetes (T2D) is a worldwide health problem, ranked as one of the leading causes for severe morbidity and premature mortality in modern society. Management of blood glucose is of major importance in order to limit the severe outcomes of the disease. However, despite the impressive success in the development of new antidiabetic drugs, almost no progress has been achieved with regard to the development of novel insulin-sensitizing agents. As insulin resistance is the most eminent factor in the patho-etiology of T2D, it is not surprising that an alarming number of patients still fail to meet glycemic goals. Owing to its wealth of chemical structures, the plant kingdom is considered as an inventory of compounds exerting various bioactivities, which might be used as a basis for the development of novel medications for various pathologies. Antidiabetic activity is found in over 400 plant species, and is attributable to varying mechanisms of action. Nevertheless, relatively limited evidence exists regarding phytochemicals directly activating insulin signaling, which is the focus of this review. Here, we will list plants and phytochemicals that have been found to improve insulin sensitivity by activation of the insulin signaling cascade, and will describe the active constituents and their mechanism of action.

Insulin-sensitizing and insulin-mimetic activities of Sarcopoterium spinosum extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Sarcopoterium spinosum is an abundant plant in Israel, used by Bedouin medicinal practitioners for the treatment of diabetes. In our previous study we validated the anti-diabetic activity of Sarcopoterium spinosum. The aim of this study was to further clarify its mechanism of action. MATERIALS AND METHODS: In-vivo studies were performed on KK-a/y mice given the extract for 6 weeks. Insulin tolerance test was performed, and relative pancreatic islets area was measured. Mechanisms of action were investigated in L6 myotubes using protein array, Western blot analysis and confocal microscopy. Glucose uptake assays were performed in 3T3-L1 adipocytes. RESULTS: Sarcopoterium spinosum extract reduced fasting blood glucose and improved insulin sensitivity in treated mice. Hypertrophic islets were detected in diabetic, but not in Sarcopoterium spinosum-treated mice. Sarcopoterium spinosum phosphorylated PTEN on ser380 and thr382/383, which are known inhibitory sites. PKB was not phosphorylated by Sarcopoterium spinosum, however, translocation of PKB from cytoplasm to the membrane and nucleus was detected. Target proteins of PKB were regulated by Sarcopoterium spinosum; GSK3ß was phosphorylated and cytosolic localization of FoxO was increased. Glucose uptake was increased in a PI3K and AMPK-independent mechanism. CONCLUSIONS: We suggest that Sarcopoterium spinosum inhibited PTEN and activated PKB by a mechanism which is independent of ser473 and thr308 phosphorylation. Other post translation modifications might be involved and should be analyzed further in order to understand this unique PKB activation. Identifying the active molecules in the extract, may lead to the development of new agents for the treatment of insulin resistance.

Sarcopoterium spinosum extract as an antidiabetic agent: in vitro and in vivo study.

ETHNOPHARMACOLOGICAL RELEVANCE: Sarcopoterium spinosum (L.) sp., a common plant in the Mediterranean region, is widely used as an antidiabetic drug by Bedouin healers. However, the antidiabetic properties of Sarcopoterium spinosum had not been fully validated using scientific tools. AIM OF THE STUDY: To determine the effectiveness of Sarcopoterium spinosum extract as an antidiabetic agent in vitro and in vivo. MATERIALS AND METHODS: RINm pancreatic beta-cells, L6 myotubes, 3T3-L1 adipocytes and AML-12 hepatocytes were treated with an aqueous Sarcopoterium spinosum extract (0.001-10mg/ml). The effect of the extract on specific physiological functions, including insulin secretion, pancreatic beta-cell viability, GSK3 beta phosphorylation, lipolysis and glucose uptake was measured. In vivo studies were performed using KK-A(y) mice, given the extract for several weeks. IPGTT was performed, and plasma insulin, FFA, food consumption and body weight were measured. In addition, diabetic KK-A(y) mice were given a single dose of the extract, and IPGTT was performed. RESULTS: Sarcopoterium spinosum extract increased basal and glucose/forskolin-induced insulin secretion in RINm cells, and increased cell viability. The extract inhibited lipolysis in 3T3-L1 adipocytes, and induced glucose uptake in these cells as well as in AML-12 hepatocytes and L6 myotubes. GSK3 beta phosphorylation was also induced in L6 myotubes, suggesting increased glycogen synthesis. Sarcopoterium spinosum extract had a preventive effect on the progression of diabetes in KK-A(y) mice. Catechin and epicatechin were detected in Sarcopoterium spinosum extract using hyphenated LC-MS/MS. CONCLUSIONS: Sarcopoterium spinosum extract has effects that mimic those of insulin and provide the basis for antidiabetic activity of the extract.